Hepatocellular Carcinoma (HCC) is increasing in frequency and mortality in United States, and the rapid increase of HCC incidence correlates with increase in hepatitis viral infection. Early diagnosis and accurate assessment of treatment response require a reliable, localized, repeatable, and quantitative measure. Medical imaging offers such a means for non-invasive, repeated, and quantitative evaluation of the progression or status of HCC. However, the main PET tracer currently used for oncology imaging, [18F]-FDG, has been shown to be ineffective for imaging HCC since many HCCs do not show FDG uptake in contrast to the surrounding hepatic tissues, which has led to a high false negative rate. Other tracers such as [11C]- Acetate and [11C]-Choline have shown some uptake in HCC although the utilities of these existing tracers are still unclear. There is an urgent need for an effective imaging tracer that can be used in HCC for early detection and assessment of early response to treatment. In this application, we propose to study a new radiolabeled PET tracer L-FMAU for its performance in HCC imaging. The molecule was developed initially as an anti-viral agent. Its mirrored stereoisomer, D-FMAU, a nucleoside analog, has been labeled for PET imaging although its usefulness for imaging primary liver cancer such as HCC is in doubt due to the high background uptake in the liver. L-FMAU, on the other hand, is a non-natural nucleoside analog and has been the focal interest of recent radiolabeling development for PET imaging. There is a real potential for L-FMAU to be a PET tracer for imaging HCC based on our preliminary results. We will conduct thorough investigations for the mechanisms responsible for L-FMAU's transport, metabolism, degradation (or resistance to it) in the liver tissue and liver cancer, and will correlate PET imaging data with characteristics of the cancer to evaluate L-FMAU's utility i imaging HCC. PUBLIC HEALTH RELEVANCE: Our study evaluates a new PET tracer for effective imaging of hepatocellular carcinoma (HCC). FDG, the available PET tracer commonly used for oncological applications, is ineffective for HCC imaging due to a high false negative rate. The new imaging tracer, L- FMAU has shown great promise. We will investigate the molecular mechanisms for its use in liver cancer imaging. Specifically, we will examine its performance for early detection and assessment of early response to the treatment of HCC. Upon successful development and evaluation as proposed, the use of this new tracer will meet the urgent need for effective PET imaging for HCC, which is increasing rapidly in frequency and mortality in United States.